4-hydroxybutyric acid analogs

ABSTRACT

This invention relates to novel derivatives of 4-hydroxybutyric acid and prodrugs thereof, and pharmaceutically acceptable salts of the foregoing. This invention also provides pharmaceutical compositions comprising a compound of this invention and the use of such compositions in methods of treating narcolepsy, fibromyalgia, other disorders or conditions that are beneficially treated by improving nocturnal sleep or by administering sodium oxybate.

RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 61/214,382,filed Apr. 23, 2009 and U.S. Application No. 61/287,561, filed Dec. 17,2009. The entire teachings of the above applications are incorporatedherein by reference.

BACKGROUND OF THE INVENTION

4-Hydroxybutyric acid is a well-known hypnotic agent. Though itsmechanism of action is poorly understood, 4-hydroxybutyrate has beencharacterized as inhibiting polysynaptic reflexes while retainingmonosynaptic reflexes. It typically induces sleep while maintaining goodrespiration (Basil, B. et al., Br J Pharmacol Chemother, 1964, 22:318and increases delta sleep (stage 3 and stage 4) while decreasing lightor stage 1 sleep (Scrima, L. et al., Sleep, 1990, 13:479; Pardi, D. andBlack, J., CNS Drugs, 2006, 20:993.

The sodium salt of 4-hydroxybutyric acid, known generically as sodiumoxybate and marketed as Xyrem®, is approved for the treatment ofexcessive daytime sleepiness and cataplexy in patients with narcolepsy.It is effective for relieving pain and improving function in patientswith fibromyalgia syndrome (Scharf, M B et al., J Rheumatol, 2003,30:1070; Russell, I J et al., Arthritis Rheum 2009, 60:299). Sodiumoxybate has also been reported to be effective in alleviating excessivedaytime sleepiness and fatigue in patients with Parkinson's disease,improving myoclonus and essential tremor, and reducing tardivedyskinesia and bipolar disorder (Ondo, W G et al., Arch Neurol, 2008,65:1337; Frucht, S J et al, Neurology, 2005, 65:1967; Berner, J E, JClin Psychiatry, 2008, 69:862).

Despite a general record of safety when used as prescribed, impairedrespiration has been reported in some patients following a typical doseof sodium oxybate (see, e.g., FDA product label dated Nov. 13, 2006 forNDA no. 021196). Headache, nausea, and dizziness were observed inclinical trials at rates of 17-22%. These adverse effects weredose-dependent.

The use of 4-hydroxybutyric acid can be inconvenient because of its veryshort half life in humans (0.5-1 hour). Many patients report needing totake two separate doses of the drug during the night to maintain sleep.Consequently, despite the desirable and beneficial effects of4-hydroxybutyric acid, there is a continuing need for new compounds totreat the aforementioned diseases and conditions.

SUMMARY OF THE INVENTION

This invention relates to novel derivatives of 4-hydroxybutyric acid andprodrugs thereof, and pharmaceutically acceptable salts of theforegoing. This invention also provides pharmaceutical compositionscomprising a compound of this invention and the use of such compositionsin methods of selectively inhibiting polysynaptic reflexes withoutsignificantly affecting monosynaptic reflexes, and treating narcolepsy,fibromyalgia, other disorders and conditions that are beneficiallytreated by improving nocturnal sleep or by administering sodium oxybate.

DETAILED DESCRIPTION

The term “treat” as used herein means decrease, suppress, attenuate,diminish, arrest, or stabilize the development or progression of adisease (e.g., a disease or disorder delineated herein), lessen theseverity of the disease or improve the symptoms associated with thedisease.

“Disease” means any condition or disorder that damages or interfereswith the normal function of a cell, tissue, or organ.

It will be recognized that some variation of natural isotopic abundanceoccurs in a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. Thus, a preparation of sodium oxybatewill inherently contain small amounts of deuterated isotopologues. Theconcentration of naturally abundant stable hydrogen and carbon isotopes,notwithstanding this variation, is small and immaterial as compared tothe degree of stable isotopic substitution of compounds of thisinvention. See, for instance, Wada, E et al., Seikagaku, 1994, 66:15;Gannes, L Z et al., Comp Biochem Physiol Mol Integr Physiol, 1998,119:725.

In the compounds of this invention any atom not specifically designatedas a particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Also unlessotherwise stated, when a position is designated specifically as “D” or“deuterium”, the position is understood to have deuterium at anabundance that is at least 3340 times greater than the natural abundanceof deuterium, which is 0.015% (i.e., at least 50.1% incorporation ofdeuterium).

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope.

In other embodiments, a compound of this invention has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation).

The term “isotopologue” refers to a species that differs from a specificcompound of this invention only in the isotopic composition thereof.

The term “compound,” when referring to a compound of this invention,refers to a collection of molecules having an identical chemicalstructure, except that there may be isotopic variation among theconstituent atoms of the molecules. Thus, it will be clear to those ofskill in the art that a compound represented by a particular chemicalstructure containing indicated deuterium atoms, will also contain lesseramounts of isotopologues having hydrogen atoms at one or more of thedesignated deuterium positions in that structure. The relative amount ofsuch isotopologues in a compound of this invention will depend upon anumber of factors including the isotopic purity of deuterated reagentsused to make the compound and the efficiency of incorporation ofdeuterium in the various synthesis steps used to prepare the compound.However, as set forth above the relative amount of such isotopologues intoto will be less than 49.9% of the compound. In other embodiments, therelative amount of such isotopologues in toto will be less than 47.5%,less than 40%, less than 32.5%, less than 25%, less than 17.5%, lessthan 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% ofthe compound.

The invention also provides salts of the compounds of the invention.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another embodiment, the compound is apharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention. A “pharmaceutically acceptable counterion”is an ionic portion of a salt that is not toxic when released from thesalt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide, hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, aswell as organic acids such as para-toluenesulfonic acid, salicylic acid,tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylicacid, fumaric acid, gluconic acid, glucuronic acid, formic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonicacid, carbonic acid, succinic acid, citric acid, benzoic acid and aceticacid, as well as related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, sulfonate, xylene sulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and othersalts. In one embodiment, pharmaceutically acceptable acid additionsalts include those formed with mineral acids such as hydrochloric acidand hydrobromic acid, and especially those formed with organic acidssuch as maleic acid.

The pharmaceutically acceptable salt may also be a salt of a compound ofthe present invention having an acidic functional group, such as acarboxylic acid functional group, and a base. Exemplary bases include,but are not limited to, hydroxide of alkali metals including sodium,potassium, and lithium; hydroxides of alkaline earth metals such ascalcium and magnesium; hydroxides of other metals, such as aluminum andzinc; ammonia, organic amines such as unsubstituted orhydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-OH—(C₁-C₆)-alkylamine), such asN,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine;pyrrolidine; and amino acids such as arginine, lysine, and the like.

The compounds of the present invention (e.g., compounds of Formula I),may contain an asymmetric carbon atom, for example, as the result ofdeuterium substitution or otherwise. As such, compounds of thisinvention can exist as either individual enantiomers, or mixtures of thetwo enantiomers. Accordingly, a compound of the present invention mayexist as either a racemic mixture or a scalemic mixture, or asindividual respective stereoisomers that are substantially free fromanother possible stereoisomer. The term “substantially free of otherstereoisomers” as used herein means less than 25% of otherstereoisomers, preferably less than 10% of other stereoisomers, morepreferably less than 5% of other stereoisomers and most preferably lessthan 2% of other stereoisomers, or less than “X”% of other stereoisomers(wherein X is a number between 0 and 100, inclusive) are present.Methods of obtaining or synthesizing an individual enantiomer for agiven compound are known in the art and may be applied as practicable tofinal compounds or to starting material or intermediates.

Unless otherwise indicated, when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound.

The term “stable compounds,” as used herein, refers to compounds whichpossess stability sufficient to allow for their manufacture and whichmaintain the integrity of the compound for a sufficient period of timeto be useful for the purposes detailed herein (e.g., formulation intotherapeutic products, intermediates for use in production of therapeuticcompounds, isolatable or storable intermediate compounds, treating adisease or condition responsive to therapeutic agents).

“D” and “d” both refer to deuterium. Unless otherwise indicated,“stereoisomer” refers to both enantiomers and diastereomers.

The term “optionally substituted with deuterium” means that one or morehydrogen atoms in the referenced moiety may be replaced with acorresponding number of deuterium atoms.

The term “C₂₋₁₀ alkoxyalkyl” refers to a moiety of the formula—(CH₂)_(a)—O—(CH₂)_(b), wherein each of a and b is an integer between 1and 9; and the sum of a+b is an integer between 2 and 10.

Throughout this specification, a variable may be referred to generally(e.g., “each R”) or may be referred to specifically (e.g., R¹, R², R³,etc.). Unless otherwise indicated, when a variable is referred togenerally, it is meant to include all specific embodiments of thatparticular variable.

Therapeutic Compounds

The present invention provides a compound of Formula B:

or a pharmaceutically acceptable salt thereof, wherein:

A¹ is hydrogen, deuterium, —CH₂—C(O)OR^(2′) or —CH(R^(1′))—C(O)OR^(2′);

R^(1′) is C₁₋₆ alkyl, C₂₋₁₀ alkoxyalkyl, phenyl, —(C₁₋₃ alkyl)-(C₃₋₆cycloalkyl), or C₃₋₆ cycloalkyl, wherein R^(1′) is optionallysubstituted with C₁₋₃ alkyl, C₁₋₃ alkoxy, phenyl, or—O—(CH₂CH₂O)_(n)—CH₃, wherein n is 1, 2, or 3;

R^(2′) is hydrogen; deuterium; —C₁₋₄ alkyl optionally substituted withphenyl; —(C₃₋₆ cycloalkyl) optionally substituted with phenyl or methyl;—CH₂—(C₃₋₆ cycloalkyl) wherein the C₃₋₆ cycloalkyl is optionallysubstituted with phenyl; phenyl; or biphenyl;

X¹ is hydrogen, deuterium, —C(O)-indanyl, —C(O)-indenyl,—C(O)-tetrahydronaphthyl, —C(O)—C₁₋₆ alkyl, —C(O)—C₁₋₆ alkenyl,—C(O)—C₁₋₆ alkynyl, —C(O)—C₁₋₃ alkyl optionally substituted with C₃₋₆cycloalkyl, or —C(O)—C₃₋₆ cycloalkyl optionally substituted with C₁₋₆alkyl, phenyl or naphthyl; and

each Y is independently selected from hydrogen and deuterium,

provided that:

(i) when A¹ is hydrogen or deuterium, at least one Y is deuterium; and

(ii) when X¹ is hydrogen or deuterium, each Y² is deuterium, and each Y³is deuterium, then A¹ is not hydrogen or deuterium.

In one embodiment of Formula B, at least one Y is deuterium. In oneaspect of this embodiment, X¹ is not hydrogen or deuterium.

In one embodiment of Formula B, R^(2′) is hydrogen, —C₁₋₄ alkyl, —C₃₋₆cycloalkyl, —CH₂—(C₃₋₆ cycloalkyl), phenyl or benzyl, and at least one Yis deuterium.

In a more specific embodiment of a compound of Formula B, A¹ is—CH₂—C(O)OR^(2′) or —CH(R^(1′))—C(O)OR^(2′); R^(1′) is C₁₋₄ alkyl; eachY¹ is the same; each Y² is the same; each Y³ is hydrogen; X¹ ishydrogen, —C(O)CH₃, or —C(O)CH₂Ph, provided that at least one of Y¹ andY² is deuterium. In one aspect of this embodiment, R^(2′) is —CH₃,—CH₂CH₃, or benzyl.

In another embodiment of Formula B: A¹ is hydrogen; each Y¹ is the same;each Y² is the same; each Y³ is hydrogen; and X¹ is selected from acetyland benzoyl, provided that at least one of Y¹ and Y² is deuterium. Inone aspect of this embodiment, each Y¹ is deuterium.

In one embodiment of Formula B, A¹ is —CH(R^(1′))—C(O)OR^(2′), thecompound having the structure of Formula B-II:

or a pharmaceutically acceptable salt thereof, wherein X¹, Y, R^(1′) andR^(2′) are as described above for Formula B.

In compounds of Formula B-II, the carbon atom bearing R^(1′) has achiral center. In one embodiment, the compound of Formula B-II has the(S) configuration at that chiral center as shown in Formula (S)-B-IIbelow.

In certain embodiments of compounds of Formula B, B-II and (S)-B-II,each Y¹ is the same; each Y² is the same; and each Y³ is the same, andat least one pair of Y (e.g., each Y¹; each Y²; or each Y³) isdeuterium. In one specific aspect, each Y³ is hydrogen.

Another embodiment of Formula B provides a compound wherein each Y³ ishydrogen and A¹ is —CH₂—C(O)OR^(2′), the compound having the structureshown in Formula B-III:

or a pharmaceutically acceptable salt thereof, wherein the X¹, Y andR^(2′) variables are as described above for Formula B.

In certain embodiments of compounds of Formula B-III, each Y¹ is thesame; each Y² is the same; and each Y³ is the same, and at least onepair of Y (e.g., each Y¹; each Y²; or each Y³) is deuterium. In onespecific aspect, each Y³ is hydrogen.

The present invention also provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is hydrogen, deuterium, —CH₂—C(O)OR² or —CH(R¹)—C(O)OR²;

R¹ is a C₁₋₆ alkyl, C₂₋₁₀ alkoxyalkyl, or C₃₋₆ cycloalkyl group that isoptionally substituted by an R³ group;

R³ is C₁₋₃ alkyl, C₁₋₃ alkoxy, phenyl, —O—(CH₂CH₂O)_(n)—CH₃, or-(heterocyclyl)-C₁₋₃ alkyl where the heterocyclyl moiety is a four tosix-membered ring having an oxygen ring atom;

n is 1, 2, or 3;

R² is hydrogen, deuterium, —C₁₋₄ alkyl, —C₁₋₄ alkyl-phenyl, —C₃₋₆cycloalkyl, —C₃₋₆ cycloalkyl-phenyl, —CH₂—(C₃₋₆ cycloalkyl), —CH₂—(C₃₋₆cycloalkyl)-phenyl, phenyl, or biphenyl;

X is hydrogen, deuterium, —C(O)-indanyl, —C(O)-indenyl,—C(O)-tetrahydronaphthyl, —C(O)—C₁₋₆ alkyl, —C(O)—C₁₋₆ alkenyl,—C(O)—C₁₋₆ alkynyl, —C(O)—C₁₋₃ alkyl-(C₃₋₆ cycloalkyl), or —C(O)—C₃₋₆cycloalkyl optionally substituted by C₁₋₆ alkyl, phenyl or naphthyl; and

each Y is independently selected from hydrogen and deuterium,

provided that when A is hydrogen at least one Y is deuterium.

In one embodiment of Formula I, each Y is independently selected fromhydrogen and deuterium, provided that when A is hydrogen at least one Yis deuterium and X is not hydrogen.

Examples of the R³ heterocyclyl moiety of Formula I include oxetane,tetrahydrofuran, furan, tetrahydropyran and pyran.

In one embodiment of Formula I, R² is hydrogen, —C₁₋₄ alkyl, —C₃₋₆cycloalkyl, —CH₂—(C₃₋₆ cycloalkyl), phenyl or benzyl.

In a more specific embodiment of a compound of Formula I A is—CH₂—C(O)OR² or —CH(R¹)—C(O)OR²; R¹ is C₁₋₄ alkyl; each Y¹ is the same;each Y² is the same; each Y³ is hydrogen; X is hydrogen, —C(O)CH₃, or—C(O)CH₂Ph. In one aspect of this embodiment, R² is —CH₃, —CH₂CH₃, orbenzyl.

In another embodiment of Formula I: A is hydrogen; each Y¹ is the same;each Y² is the same; each Y³ is hydrogen; and X is selected from acetyland benzoyl. In one aspect of this embodiment, each Y¹ is deuterium.

In one embodiment of Formula I, A is —CH(R¹)—C(O)OR², the compoundhaving the structure of Formula II:

or a pharmaceutically acceptable salt thereof, wherein X, Y, R¹ and R²are as described above for Formula I.

In compounds of Formula II, the carbon atom bearing R¹ has a chiralcenter. In one embodiment, the compound of Formula II has the (S)configuration at that chiral center as shown in Formula (S)-II below.

In certain embodiments of compounds of Formula I, II and S-II, each Y¹is the same; each Y² is the same; and each Y³ is the same. In onespecific aspect, each Y³ is hydrogen.

Another embodiment of Formula II provides a compound wherein each Y³ ishydrogen and R¹ is hydrogen, the compound having the structure shown inFormula III:

or a pharmaceutically acceptable salt thereof, wherein the X, Y and R²variables are as described above for Formula I.

Table 1 shows examples of specific compounds of Formula III.

TABLE 1 Examples of Specific Compounds of Formula III Compound # X EachY¹ Each Y² R² 100 H H H CH₃ 101 H H H C₂H₅ 102 H H H CH₂C₆H₅ 103 H D HCH₃ 104 H D H C₂H₅ 105 H D H CH₂C₆H₅ 106 H H D CH₃ 107 H H D C₂H₅ 108 HH D CH₂C₆H₅ 109 Ac H H CH₃ 110 Ac H H C₂H₅ 111 Ac H H CH₂C₆H₅ 112 Ac D HCH₃ 113 Ac D H C₂H₅ 114 Ac D H CH₂C₆H₅ 115 Ac H D CH₃ 116 Ac H D C₂H₅117 Ac H D CH₂C₆H₅ 118 H H H H

In certain embodiments, the compound of Formula III is apharmaceutically acceptable salt of any one of the compounds set forthin Table 1.

In another embodiment the invention provides a compound selected fromany one of

or a pharmaceutically acceptable salt thereof.

In another embodiment the invention provides the compound

or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the invention provides a compound selectedfrom any one of HO—CH₂—CH₂—CD₂-C(O)—O⁻Na⁺, HO—CH₂—CD₂-CD₂-C(O)—O⁻Na⁺,and HO—CH₂—CD₂-CH₂—C(O)—O⁻Na⁺.

In another set of embodiments, any atom not designated as deuterium inany of the embodiments set forth above is present at its naturalisotopic abundance.

In one embodiment the invention provides any one of the followingcompounds, where any atom not designated as deuterium is present in itsnatural abundance:

or a pharmaceutically acceptable salt of any of the foregoing.

The synthesis of compounds of Formula I can be readily achieved bysynthetic chemists of ordinary skill. Relevant procedures andintermediates such as methyl, ethyl, and benzyl lactate esters, as wellas acetic anhydride and benzoic anhydride are commercially available.Methods for esterifying alcohols are described in Greene T W et al.,Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons(1999).

Such methods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure.

Exemplary Synthesis

A convenient method for synthesizing compounds of Formula I is depictedin Scheme 1.

Compounds of this invention can readily be made by means known in theart of organic synthesis.

Scheme 1 shows a general method for making compounds of Formula I.Alkylation of the alcohol group of an appropriately deuteratedtert-butyl ester of 4-hydroxybutyric acid 10 is achieved by means knownin the art, for instance by using benzyl bromide as an alkylating agentwith potassium carbonate as a base in an aprotic solvent to produce thebenzyl ester 11. Acidolytic removal of the tert-butyl group, forinstance by using excess anhydrous hydrogen chloride dissolved in aninert solvent, produces the corresponding acid 12. Esterification of theresulting acid 12 with an appropriate ester 13 usingdicyclohexylcarbodiimide (“DCC”) with catalytic 4-dimethylaminepyridine(“4-DMAP”) produces the corresponding diester 14. The benzyl group isthen removed by catalytic hydrogenation using palladium hydroxide as thecatalyst to produce a compound of Formula I, wherein X is hydrogen.Acetylation of this compound of Formula I using an anhydride and atertiary amine base such as diisopropylethylamine (“DIPEA”) produces acompound of Formula I, where X is —C(O)—C₁-C₆ alkyl.

Scheme 2 shows a method for the regioselective deuteration of the 2position of commercially available 4-hydroxybutyric acid tert-butylester (10) to yield the 2,2-dideutero species (10-d2). Reaction with adeuterium donor such as D₂O, optionally using a co-solvent such as THF,and a base such K₂CO₃ provides 4-hydroxybutyrate compounds where each Y¹is deuterium. In order to obtain the desired level of deuteriumsubstitution, several such exchange reactions may be carried out insequence. Such a sequence may provide deuterium incorporation of atleast 90% and typically greater than 95% at each Y¹ position. Theresulting selectively deuterated compound can then be carried throughthe reaction sequence specified in Scheme 1 to produce compounds ofFormula I, wherein each Y¹ is deuterium.

Scheme 3 shows a method for selective deuterium substitution at the3-position (Y²). Deuterium substitution of commercially available benzyl4-hydroxybutyrate (20), using (CH₃)₃OD and a small amount of C₆H₅CH₂ODas deuterium donors, and a base such as K₂CO₃, produces the2,2-dideutero alcohol species 21. The oxidation of the alcohol 21 usingruthenium tetroxide under neutral conditions produces the carboxylicacid 22. Tert-butyl esterification of the carboxylic acid 22 using DCCwith a catalytic amount of 4-dimethylaminepyridine and tert-butylalcohol is followed by cleavage of the benzyl ester by catalytichydrogenation using palladium hydroxide to produce the t-butoxycarboxylic acid 23. Selective reduction of the carboxylic acid 23 usingborane in THF complex produces 3,3-dideutero-4-hydroxybutyric acidtert-butyl ester (10-3,3-d2), which can be used in Scheme 1 to producecompound of Formula I, wherein Y³ is deuterium.

The specific approaches and compounds shown above are not intended to belimiting. The chemical structures in the schemes herein depict variablesthat are hereby defined commensurately with chemical group definitions(moieties, atoms, etc.) of the corresponding position in the compoundformulae herein, whether identified by the same variable name (i.e., R¹,R², R³, etc.) or not. The suitability of a chemical group in a compoundstructure for use in the synthesis of another compound is within theknowledge of one of ordinary skill in the art.

Analogous methods to the ones shown in Schemes 1-3 for compounds ofFormula I may be used for synthesizing compounds of Formula B as.

Additional methods of synthesizing compounds of Formula I or Formula Band their synthetic precursors, including those within routes notexplicitly shown in schemes herein, are within the means of chemists ofordinary skill in the art. Synthetic chemistry transformations andprotecting group methodologies (protection and deprotection) useful insynthesizing the applicable compounds are known in the art and include,for example, those described in Larock R, Comprehensive OrganicTransformations, VCH Publishers (1989); Greene T W et al., ProtectiveGroups in Organic Synthesis, 3^(rd) Ed., John Wiley and Sons (1999);Fieser L et al., Fieser and Fieser's Reagents for Organic Synthesis,John Wiley and Sons (1994); and Paquette L, ed., Encyclopedia ofReagents for Organic Synthesis, John Wiley and Sons (1995) andsubsequent editions thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds.

Compositions

The invention also provides pyrogen-free pharmaceutical compositionscomprising an effective amount of a compound of Formula I (e.g.,including any of the compounds of formulae II, (S)-II, or III herein) orFormula B, B-II, (S)-B-II or B-III, or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable carrier. The carrier(s)are “acceptable” in the sense of being compatible with the otheringredients of the formulation and, in the case of a pharmaceuticallyacceptable carrier, not deleterious to the recipient thereof in anamount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

If required, the solubility and bioavailability of the compounds of thepresent invention in pharmaceutical compositions may be enhanced bymethods well-known in the art. One method includes the use of lipidexcipients in the formulation. See “Oral Lipid-Based Formulations:Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs andthe Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare,2007; and “Role of Lipid Excipients in Modifying Oral and ParenteralDrug Delivery: Basic Principles and Biological Examples,” Kishor M.Wasan, ed. Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of anamorphous form of a compound of this invention optionally formulatedwith a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), orblock copolymers of ethylene oxide and propylene oxide. See U.S. Pat.No. 7,014,866; and United States patent publications 20060094744 and20060079502.

The pharmaceutical compositions of the invention include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. In certain embodiments, thecompound of the formulae herein is administered transdermally (e.g.,using a transdermal patch or iontophoretic techniques). Otherformulations may conveniently be presented in unit dosage form, e.g.,tablets, sustained release capsules, and in liposomes, and may beprepared by any methods well known in the art of pharmacy. See, forexample, Remington's Pharmaceutical Sciences, Mack Publishing Company,Philadelphia, Pa. (17th ed. 1985).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers, or both, and then, if necessary, shapingthe product.

In certain embodiments, if a protic solvent such as water or alcohols isused to dissolve or suspend a compound of this invention in apharmaceutical composition, the solvent is preferably deuterated (e.g.D₂O, CH₃CH₂OD, CH₃CH₂OD). In these cases the proton on the hydroxygroups of the compound of Formula I or B will be partially or mostlyreplaced with deuterium. Compounds of Formula I or B comprising adeuterated hydroxy group in place of —OH are also part of the presentinvention.

In certain embodiments, the compound is administered orally.Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets, or tabletseach containing a predetermined amount of the active ingredient; apowder or granules; a solution or a suspension in an aqueous liquid or anon-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oilliquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatincapsules can be useful for containing such suspensions, which maybeneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be administered inthe form of suppositories for rectal administration. These compositionscan be prepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include, but are notlimited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art. See, e.g.: Rabinowitz J D and Zaffaroni A C, U.S. Pat. No.6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For topicalapplication topically to the skin, the pharmaceutical composition shouldbe formulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches andiontophoretic administration are also included in this invention.

Application of the subject therapeutics may be local, so as to beadministered at the site of interest. Various techniques can be used forproviding the subject compositions at the site of interest, such asinjection, use of catheters, trocars, projectiles, pluronic gel, stents,sustained drug release polymers or other device which provides forinternal access.

Thus, according to yet another embodiment, the compounds of thisinvention may be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents, or catheters. Suitable coatings and the generalpreparation of coated implantable devices are known in the art and areexemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccharides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics in thecomposition. Coatings for invasive devices are to be included within thedefinition of pharmaceutically acceptable carrier, adjuvant or vehicle,as those terms are used herein.

According to another embodiment, the invention provides a method ofcoating an implantable medical device comprising the step of contactingsaid device with the coating composition described above. It will beobvious to those skilled in the art that the coating of the device willoccur prior to implantation into a mammal.

According to another embodiment, the invention provides a method ofimpregnating an implantable drug release device comprising the step ofcontacting said drug release device with a compound or composition ofthis invention. Implantable drug release devices include, but are notlimited to, biodegradable polymer capsules or bullets, non-degradable,diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, the invention provides an implantablemedical device coated with a compound or a composition comprising acompound of this invention, such that said compound is therapeuticallyactive.

According to another embodiment, the invention provides an implantabledrug release device impregnated with or containing a compound or acomposition comprising a compound of this invention, such that saidcompound is released from said device and is therapeutically active.

Where an organ or tissue is accessible because of removal from thepatient, such organ or tissue may be bathed in a medium containing acomposition of this invention, a composition of this invention may bepainted onto the organ, or a composition of this invention may beapplied in any other convenient way.

In another embodiment, a composition of this invention further comprisesa second therapeutic agent. The second therapeutic agent may be selectedfrom any compound or therapeutic agent known to have or thatdemonstrates advantageous properties when administered with sodiumoxybate.

In one embodiment, the second therapeutic agent is useful in thetreatment of abnormal nocturnal sleep, and conditions beneficiallytreated by improving nocturnal sleep, such as narcolepsy, andfibromyalgia. In another embodiment, the second therapeutic agent isuseful in selectively inhibiting polysynaptic reflexes in a patientwithout significantly affecting monosynaptic reflexes.

In another embodiment, the second therapeutic agent is selected fromdual serotonin-norepinephrine reuptake inhibitors and alpha2-deltasubunit calcium channel modulators.

Examples of dual serotonin-norepinephrine reuptake include, but are notlimited to, duloxetine, milnacipran, and venlafaxine.

Examples of alpha2-delta subunit calcium channel modulators include, butare not limited to, pregabalin, gabapentin, and prodrugs thereof.

In another embodiment, the invention provides separate dosage forms of acompound of this invention and one or more of any of the above-describedsecond therapeutic agents, wherein the compound and second therapeuticagent are associated with one another. The term “associated with oneanother” as used herein means that the separate dosage forms arepackaged together or otherwise attached to one another such that it isreadily apparent that the separate dosage forms are intended to be soldand administered together (within less than 24 hours of one another,consecutively or simultaneously).

In the pharmaceutical compositions of the invention, the compound of thepresent invention is present in an effective amount. As used herein, theterm “effective amount” refers to an amount which, when administered ina proper dosing regimen, is sufficient to treat (therapeutically orprophylactically) the target disorder. For example, to reduce orameliorate the severity, duration or progression of the disorder beingtreated, prevent the advancement of the disorder being treated, causethe regression of the disorder being treated, or enhance or improve theprophylactic or therapeutic effect(s) of another therapy.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., (1966) Cancer Chemother. Rep 50: 219. Body surface area may beapproximately determined from height and weight of the patient. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.

In one embodiment, an effective amount of a compound of this inventioncan range from about 0.05-2.5 mmol of a compound of Formula I Formula Ior pharmaceutically acceptable salt thereof/kg of body weight,preferably between about 0.15-1.5 mmol/kg. When treating a human patientin need of improved nocturnal sleep, the selected dose is preferablyadministered orally from 1-2 times daily. More preferably the selecteddose is administered orally 1 time daily.

Effective doses will also vary, as recognized by those skilled in theart, depending on the diseases treated, the severity of the disease, theroute of administration, the sex, age and general health condition ofthe patient, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician. For example, guidance for selecting an effectivedose can be determined by reference to the prescribing information forsodium oxybate.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 20% and 100% of the dosage normally utilized in a monotherapyregime using just that agent. Preferably, an effective amount is betweenabout 70% and 100% of the normal monotherapeutic dose. The normalmonotherapeutic dosages of these second therapeutic agents are wellknown in the art. See, e.g., Wells et al., eds., PharmacotherapyHandbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), each of which referencesare incorporated herein by reference in their entirety.

It is expected that some of the second therapeutic agents referencedabove will act synergistically with the compounds of this invention.When this occurs, it will allow the effective dosage of the secondtherapeutic agent and/or the compound of this invention to be reducedfrom that required in a monotherapy. This has the advantage ofminimizing toxic side effects of either the second therapeutic agent ofa compound of this invention, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Methods of Treatment

According to another embodiment, the invention provides a method oftreating a disease or condition that is beneficially treated by a sodiumoxybate in a patient in need thereof, comprising the step ofadministering to the patient an effective amount of a compound or acomposition of this invention. Such diseases and conditions include, butare not limited to, abnormal nocturnal sleep, and conditionsbeneficially treated by improving nocturnal sleep, such as narcolepsy,and fibromyalgia. In another embodiment, the method is used toselectively inhibit polysynaptic reflexes in a patient withoutsignificantly affecting monosynaptic reflexes.

In one particular embodiment, the method of this invention is used toimprove nocturnal sleep in a patient in need thereof.

Identifying a patient in need of such treatment can be in the judgmentof a patient or a health care professional and can be subjective (e.g.opinion) or objective (e.g. measurable by a test or diagnostic method).

In another embodiment, any of the above methods of treatment comprisesthe further step of co-administering to the patient in need thereof oneor more second therapeutic agents. The choice of second therapeuticagent may be made from any second therapeutic agent known to be usefulfor co-administration with sodium oxybate. The choice of secondtherapeutic agent is also dependent upon the particular disease orcondition to be treated. Examples of second therapeutic agents that maybe employed in the methods of this invention are those set forth abovefor use in combination compositions comprising a compound of thisinvention and a second therapeutic agent.

In particular, the combination therapies of this invention includeco-administering a compound of Formula I or Formula B orpharmaceutically acceptable salt thereof and a second therapeutic agentto a patient in need thereof selected from dual serotonin-norepinephrinereuptake inhibitors and alpha2-delta subunit calcium channel modulators.

In one embodiment, the second therapeutic agent is a dualserotonin-norepinephrine reuptake selected from duloxetine, milnacipran,and venlafaxine.

In another embodiment, the second therapeutic agent is an alpha2-deltasubunit calcium channel modulators selected from pregabalin, gabapentin,and prodrugs thereof.

The term “co-administered” as used herein means that the secondtherapeutic agent may be administered together with a compound of thisinvention as part of a single dosage form (such as a composition of thisinvention comprising a compound of the invention and an secondtherapeutic agent as described above) or as separate, multiple dosageforms. Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of a compound ofthis invention. In such combination therapy treatment, both thecompounds of this invention and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of this invention, comprising both a compound of theinvention and a second therapeutic agent, to a patient does not precludethe separate administration of that same therapeutic agent, any othersecond therapeutic agent or any compound of this invention to saidpatient at another time during a course of treatment.

Effective amounts of these second therapeutic agents are well known tothose skilled in the art and guidance for dosing may be found in patentsand published patent applications referenced herein, as well as in Wellset al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),and other medical texts. However, it is well within the skilledartisan's purview to determine the second therapeutic agent's optimaleffective-amount range.

In one embodiment of the invention, where a second therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount would be where the secondtherapeutic agent is not administered. In another embodiment, theeffective amount of the second therapeutic agent is less than itseffective amount would be where the compound of this invention is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art.

In yet another aspect, the invention provides the use of a compound ofFormula I Formula I or pharmaceutically acceptable salt thereof alone ortogether with one or more of the above-described second therapeuticagents in the manufacture of a medicament, either as a singlecomposition or as separate dosage forms, for treatment or prevention ina patient of a disease, disorder or symptom set forth above. Anotheraspect of the invention is a compound of Formula I or pharmaceuticallyacceptable salt thereof for use in the treatment or prevention in apatient of a disease, disorder or symptom thereof delineated herein.

Pharmaceutical Kits

The present invention also provides kits for use in improving nocturnalsleep These kits comprise (a) a pharmaceutical composition comprising acompound of Formula I or Formula B, or a pharmaceutically acceptablesalt thereof, wherein said pharmaceutical composition is in a container;and (b) instructions describing a method of using the pharmaceuticalcomposition to improve nocturnal sleep.

The container may be any vessel or other sealed or sealable apparatusthat can hold said pharmaceutical composition. Examples include bottles,ampules, divided or multi-chambered holders bottles, wherein eachdivision or chamber comprises a single dose of said composition, adivided foil packet wherein each division comprises a single dose ofsaid composition, or a dispenser that dispenses single doses of saidcomposition. The container can be in any conventional shape or form asknown in the art which is made of a pharmaceutically acceptablematerial, for example a paper or cardboard box, a glass or plasticbottle or jar, a re-sealable bag (for example, to hold a “refill” oftablets for placement into a different container), or a blister packwith individual doses for pressing out of the pack according to atherapeutic schedule. The container employed can depend on the exactdosage form involved, for example a conventional cardboard box would notgenerally be used to hold a liquid suspension. It is feasible that morethan one container can be used together in a single package to market asingle dosage form. For example, tablets may be contained in a bottle,which is in turn contained within a box. In one embodiment, thecontainer is a blister pack.

The kits of this invention may also comprise a device to administer orto measure out a unit dose of the pharmaceutical composition. Suchdevice may include an inhaler if said composition is an inhalablecomposition; a syringe and needle if said composition is an injectablecomposition; a syringe, spoon, pump, or a vessel with or without volumemarkings if said composition is an oral liquid composition; or any othermeasuring or delivery device appropriate to the dosage formulation ofthe composition present in the kit.

In certain embodiment, the kits of this invention may comprise in aseparate vessel of container a pharmaceutical composition comprising asecond therapeutic agent, such as one of those listed above for use forco-administration with a compound of this invention.

EXAMPLES Example 1 Sodium 2,2-d2-4-hydroxybutyrate

Sodium 2,2-d2-4-hydroxybutyrate is prepared in the following manner:treatment of succinic anhydride with tert-butanol, N-hydroxysuccinimide,and 4-dimethylaminopyridine (4-DMAP) according to the procedure of Yao,Z-J., et al, J. Org. Chem. 2003, 68, 6679-6684 affords the succinic acidmono-tert-butyl ester. In accordance with Yao, reduction of the succinicacid with borane-dimethyl sulfide complex gives the 4-hydroxybutanoicacid tert-butyl ester. Subjecting the ester to hydrogen/deuteriumexchange by treatment with potassium carbonate in d1-methanol affordsthe 2,2-d2-4-hydroxybutanoic acid tert-butyl ester. Finally,saponification of the tert-butyl ester with sodium hydroxide ind1-methanol in a manner analogous to the procedure of Goto, G., et al,Chem. Pharm. Bull. 1985, 33, 4422-4431 affords the desired sodium2,2-d2-4-hydroxybutyrate.

Example 2 Sodium 3,3-d2-4-hydroxybutyrate

Sodium 3,3-d₂-4-hydroxybutyrate is prepared in the following manner:treatment of mono-methylsuccinate with sodium methoxide in dl-methanolin a manner analogous to the procedure of Keay, B. A., et al., J. Org.Chem. 2007, 72, 7253-7259 affords the butanedioic-2,2-d2 acid, 1-methylester. Treatment of the d2 ester in a manner analogous to Keay et al.with sodium borohydride in water affords the4,4-dideutero-dihydrofuran-2(3H)-one. Finally, saponification of thedideutro-butyrolactone with sodium hydroxide in dl-methanol in a manneranalogous to the procedure of Goto, G., et al, Chem. Pharm. Bull. 1985,33, 4422-4431 affords the desired sodium 3,3-d2-4-hydroxybutyrate.

Example 3 Sodium 2,2,3,3-d4-4-hydroxybutyrate

Sodium 2,2,3,3-d4-4-hydroxybutyrate is prepared in the following manner:treatment of 3,3,4,4-d4-tetrahydrofuran with calcium hypochlorite inacetonitrile according to the procedure of de Meijere, A. et al., Chem.Eur. J. 2007, 13, 167-177 affords the3,3,4,4-tetradeutero-dihydrofuran-2(3H)-one. Saponification of thetetradeutero-butyrolactone with sodium hydroxide in dl-methanol in amanner analogous to the procedure of Goto, G., et al, Chem. Pharm. Bull.1985, 33, 4422-4431 affords the desired sodium2,2,3,3-d4-4-hydroxybutyrate.

The above-identified deuterated 4-hydroxybutyrate sodium salts areconverted to their corresponding esters by treatment with thecorresponding alkyl halide in the presence of an aqueous base in amanner analogous to the procedure of U.S. Pat. No. 5,250,696.

Example 4 Evaluation of Metabolic Stability in Human Liver Microsomes

Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC(Lenexa, Kans.). β-nicotinamide adenine dinucleotide phosphate, reducedform (NADPH), magnesium chloride (MgCl₂), and dimethyl sulfoxide (DMSO)are purchased from Sigma-Aldrich.

Determination of Metabolic Stability: 7.5 mM stock solutions of testcompounds are prepared in DMSO. The 7.5 mM stock solutions are dilutedto 12.5 μM in acetonitrile (ACN). The 20 mg/mL human liver microsomesare diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4,containing 3 mM MgCl₂. The diluted microsomes (375 μL) are added towells of a 96-well deep-well polypropylene plate in triplicate. 10 μL ofthe 12.5 μM test compound is added to the microsomes and the mixture ispre-warmed for 10 minutes. Reactions are initiated by addition of 125 μLof pre-warmed NADPH solution. The final reaction volume is 0.5 mL andcontains 0.5 mg/mL human liver microsomes, 0.25 μM test compound, and 2mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl₂.The reaction mixtures are incubated at 37° C., and 50 μL aliquots areremoved at 0, 5, 10, 20, and 30 minutes and added to shallow-well96-well plates which contain 50 μL of ice-cold ACN with internalstandard to stop the reactions. The plates are stored at 4° C. for 20minutes after which 100 μL of water is added to the wells of the platebefore centrifugation to pellet precipitated proteins. Supernatants aretransferred to another 96-well plate and analyzed for amounts of parentcompound remaining by LC-MS/MS using an Applied Bio-systems API 4000mass spectrometer. 7-ethoxycoumarin (1 μM) is used as the positivecontrol substrate.

Data analysis: The in vitro half-lives (t_(1/2)s) for test compounds arecalculated from the slopes of the linear regression of % parentremaining (ln) vs incubation time relationship using the followingformula:

in vitro t _(1/2)=0.693/k, where k=−[slope of linear regression of %parent remaining(ln) vs incubation time]

Data analysis is performed using Microsoft Excel Software.

The metabolic stability of compounds of Formula I is tested using pooledliver microsomal incubations. Full scan LC-MS analysis is then performedto detect major metabolites. Samples of the test compounds, exposed topooled human liver microsomes, are analyzed using HPLC-MS (or MS/MS)detection. For determining metabolic stability, multiple reactionmonitoring (MRM) is used to measure the disappearance of the testcompounds. For metabolite detection, Q1 full scans are used as surveyscans to detect the major metabolites.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of the present invention andpractice the claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. It will be apparent to those of ordinary skill inthe art that various modifications and equivalents can be made withoutdeparting from the spirit and scope of the invention.

1. A compound of the Formula B:

or a pharmaceutically acceptable salt thereof, wherein: A¹ is hydrogen,deuterium, —CH₂—C(O)OR^(2′) or —CH(R^(1′))—C(O)OR^(2′); R^(1′) is C₁₋₆alkyl, C₂₋₁₀ alkoxyalkyl, phenyl, —(C₁₋₃ alkyl)-(C₃₋₆ cycloalkyl), orC₃₋₆ cycloalkyl, wherein R^(1′) is optionally substituted with C₁₋₃alkyl, C₁₋₃ alkoxy, phenyl, —O—(CH₂CH₂O)_(n)—CH₃, wherein n is 1, 2, or3; R^(2′) is hydrogen; deuterium; —C₁₋₄ alkyl optionally substitutedwith phenyl; —(C₃₋₆ cycloalkyl) optionally substituted with phenyl ormethyl; —CH₂—(C₃₋₆ cycloalkyl) wherein the C₃₋₆ cycloalkyl is optionallysubstituted with phenyl; phenyl; or biphenyl; X¹ is hydrogen, deuterium,—C(O)-indanyl, —C(O)-indenyl, —C(O)-tetrahydronaphthyl, —C(O)—C₁₋₆alkyl, —C(O)—C₁₋₆ alkenyl, —C(O)—C₁₋₆ alkynyl, —C(O)—C₁₋₃ alkyloptionally substituted with C₃₋₆ cycloalkyl, or —C(O)—C₃₋₆ cycloalkyloptionally substituted with C₁₋₆ alkyl, phenyl or naphthyl; and each Yis independently selected from hydrogen and deuterium, provided that:(i) when A¹ is hydrogen or deuterium, at least one Y is deuterium; and(ii) when X¹ is hydrogen or deuterium, each Y² is deuterium, and each Y³is deuterium, then A¹ is not hydrogen or deuterium.
 2. The compound ofclaim 1, wherein at least one Y is deuterium.
 3. The compound of claim2, wherein: R^(2′) is hydrogen, —C₁₋₄ alkyl, —C₃₋₆ cycloalkyl,—CH₂—(C₃₋₆ cycloalkyl), phenyl or benzyl.
 4. The compound of claim 1,wherein: A¹ is —CH₂—C(O)OR^(2′) or —CH(R^(1′))—C(O)OR^(2′); R^(1′) isC₁₋₄ alkyl; each Y¹ is the same; each Y² is the same; each Y³ ishydrogen; X¹ is hydrogen, —C(O)CH₃, or —C(O)CH₂Ph; and at least one ofY¹ and Y² is deuterium.
 5. The compound of claim 4, wherein, R^(2′) is—CH₃, —CH₂CH₃, or benzyl.
 6. The compound of claim 1, wherein: A¹ ishydrogen; each Y¹ is the same; each Y² is the same; each Y³ is hydrogen;X¹ is selected from acetyl and benzoyl; and at least one of Y¹ and Y² isdeuterium.
 7. The compound of claim 6, wherein each Y¹ is deuterium. 8.The compound of claim 1, wherein A¹ is —CH(R^(1′))—C(O)OR^(2′), thecompound being represented by Formula B-II:

or a pharmaceutically acceptable salt thereof, wherein each Y¹ is thesame; each Y² is the same: and each Y³ is the same.
 9. The compound ofclaim 8, wherein the chiral carbon atom bearing R^(1′) has an (S)configuration, the compound being represented by Formula (S)-B-II:

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim9, wherein at least one pair of Y are deuterium.
 11. (canceled)
 12. Thecompound of any one of claim 1, wherein A¹ is —CH₂—C(O)OR^(2′) and eachY³ is hydrogen, the compound having the structure shown in FormulaB-III:

or a pharmaceutically acceptable salt thereof, wherein: each Y¹ is thesame; each Y² is the same; and each Y³ is the same.
 13. The compound ofclaim 12, wherein at least one pair of Y are deuterium. 14.-28.(canceled)
 29. The compound of claim 12 selected from any one of thecompounds set forth in the table below: Compound # X Each Y¹ Each Y² R²100 H H H CH₃ 101 H H H C₂H₅ 102 H H H CH₂C₆H₅ 103 H D H CH₃ 104 H D HC₂H₅ 105 H D H CH₂C₆H₅ 106 H H D CH₃ 107 H H D C₂H₅ 108 H H D CH₂C₆H₅109 Ac H H CH₃ 110 Ac H H C₂H₅ 111 Ac H H CH₂C₆H₅ 112 Ac D H CH₃ 113 AcD H C₂H₅ 114 Ac D H CH₂C₆H₅ 115 Ac H D CH₃ 116 Ac H D C₂H₅ 117 Ac H DCH₂C₆H₅ 118 H H H H

or a pharmaceutically acceptable salt of any of the foregoing.
 30. Thecompound of claim 1, selected from:

or a pharmaceutically acceptable salt thereof.
 31. The compound of claim1 having the formula:

or a pharmaceutically acceptable salt thereof.
 32. The compound of claim1, wherein any atom not designated as deuterium is present at itsnatural isotopic abundance.
 33. A pharmaceutical composition comprisinga compound of claim 1 or a pharmaceutically acceptable salt thereof; anda pharmaceutically acceptable carrier.
 34. The composition of claim 33,additionally comprising a second therapeutic agent selected from a dualserotonin-norepinephrine reuptake inhibitor and an alpha2-delta subunitcalcium channel modulator.
 35. The composition of claim 34, wherein thesecond therapeutic agent is selected from duloxetine, milnacipran,venlafaxine, pregabalin, gabapentin, and prodrugs thereof.
 36. A methodof treating a disease or disorder selected from abnormal nocturnalsleep, narcolepsy, fibromyalgia, other diseases or disordersbeneficially treated by improving nocturnal sleep or by administeringsodium oxybate comprising the step of administering to a patient in needthereof an effective amount of a composition of claim
 33. 37. The methodof claim 36 comprising the additional step of co-administering to thepatient in need thereof a second therapeutic agent selected from a dualserotonin-norepinephrine reuptake inhibitor and an alpha2-delta subunitcalcium channel modulator.
 38. The method of claim 37, wherein thesecond therapeutic agent is selected from duloxetine, milnacipran,venlafaxine, pregabalin, gabapentin, and prodrugs thereof.
 39. A methodof selectively inhibiting polysynaptic reflexes without significantlyaffecting monosynaptic reflexes in a patient in need thereof comprisingthe step of administering to the patient an effective amount of acomposition of claim 33.